Quickly gaining speed on their path to treating many
disorders in which inflammation plays a key role, researchers from the National
Institutes of Health (NIH) have created a three-dimensional depiction of the
activation of a key biological receptor (see video link above, underneath the headline for this story). According to the researchers—who
collaborated
with laboratories at the Scripps Research Institute and the
University of California, San Diego—showing this type of receptor is
"switched
on" will enable scientists to better design molecules for use in experimental
drugs to treat disease areas with high unmet medical needs,
such as arthritis,
respiratory disorders and wound healing.

In a study published in the March 10 issue
of Science Express, the researchers
show
the crystal structure of an adenosine receptor called A2A. Adenosine, which is prevalent
throughout the body, may be important in the function of
normal nerve cells, in
controlling cell proliferation and as a signal of inflammation. Of the four
adenosine receptors which detect local changes in
adenosine concentration—A1,
A2A, A2B and A3—A2A is used to sense excessive tissue inflammation.

As a member of the G protein-coupled receptor (GPCR) family,
a large protein group of transmembrane receptors that sense molecules outside
the
cell and activate inside signal transduction pathways—and ultimately,
cellular responses—A2A counteracts inflammation and responds to organs in
distress, and understanding how to "switch it on" may enable chemists to better
design new drugs for many diseases, says Dr. Kenneth A. Jacobson,
chief of the
Laboratory of Bioorganic Chemistry in NIH's National Institute of Diabetes and
Digestive and Kidney Diseases
(NIDDK), and an author on the paper.

According to Jacobson, the NIDDK has been involved in basic
research on GPCRs, an important class of drug targets, for many years, and this
recent paper is a continuation of the institute's ongoing efforts to
understand
the intricate molecular
events that lead to cellular malfunction and disease. This, researchers
believe, is the key to developing
effective treatments for some of the most
common, severe and disabling endocrine and metabolic diseases affecting
Americans today, such as such as
diabetes, obesity, hepatitis, inflammatory
bowel disease, kidney failure, prostate enlargement and anemia.

In this new study, the team led by Jacobson and his
co-author, Dr. Zhan-Guo Gao, discovered that a previously known agonist
molecule would
bind to its receptor target in a way that stabilizes the protein
for crystallization. Once crystallized, the structure can be seen by bombarding
it
with X-rays. The agonist solidifies the protein by connecting to multiple
parts of the receptor with its molecular arms, initiating the function of the
entire structure.

"Until
recently, we only had an indirect means of understanding the interaction
between the drug and its protein target," Jacobson says. "Prior to our study,
it was thought that agonist-bound structures would be too unstable or
wobbly to
form good crystals for X-ray structure determination. We showed it is possible
to crystallize a GPCR simply with an agonist—it just has to be
the appropriate
agonist. With this new structure, we can approach the design of new agonist
ligands in a more systematic and structure-based manner.
"

The architecture of the activated receptor enables
scientists to think in more detailed terms about
the other half of drug
interaction, Jacobson says—a paradigm shift discussed in his previous papers,
which met with some skepticism in the research
community.

"We hope that we're on the verge of a revolution that will
expedite the process of
crafting new drugs to treat disease," he says. "The
modeling is best served if it's based on different sources of supporting
information. That is,
one cannot expect to dock a small molecular compound
blindly in a protein without some supportive information, say, an anchor point
which may be a key
electrostatic interaction or hydrogen bond that one can
establish by mutagenesis. Once you have these supporting information, it
greatly increases the
reliability of modeling. That has been our experience."

With this finding, Jacobson and Gao will
lead their
colleagues testing this drug-engineering approach with similar molecules they
have newly synthesized. Several compounds from Jacobson's lab
are currently in
clinical trials as potential treatments for conditions including chronic
hepatitis C, psoriasis and rheumatoid arthritis. Can-Fite, an Israeli
science-based biopharmaceutical company, has licensed
several compounds from
the NIH that are in clinical trials in Europe and the United States.

The study,
"Structure of an Agonist-Bound Human A2A
Adenosine Receptor," was supported by the NIDDK's Intramural Program, which
enables basic scientists and
clinicians of diverse skills and expertise to
collaborate on solutions to some of the most difficult issues of human health.

"Discoveries like this, with the potential to lead to future
treatments in a wide variety of areas, are
why NIH funds basic science," said
NIDDK Director Dr. Griffin P. Rodgers in a statement. "By understanding the
body at its smallest components, we
can learn how to improve whole-body
health."